The term "cyclosporins" as used herein shall mean the class of nonpolar polypeptides. as defined in the Merck Index, Eleventh Edition. One such cyclosporin is cyclosporin A, also known as "cyclosporine" and hereinafter referred to as "cyclosporine", known to be therapeutically active as an immunosuppressant.
The term "composition" as used herein is to be understood as meaning any composition containing a drug along with inactive ingredients that are pharmaceutically acceptable by reason of not being excessively toxic in the quantities required.
The term "solvent system" as used herein is to be understood to mean the material in which the drug (i.e. a cyclosporin) is dissolved. The solvent system may be a single solvent or a combination or mixture of ingredients included as solvents, surfactants, diluents or for other purposes.
Cyclosporins are hydrophobic and have low solubility in aqueous media. This makes it difficult to design pharmaceutical compositions which exhibit satisfactory absorption into systemic circulation after oral administration, or absorption into the target tissue upon topical administration.
The cyclosporin can be dissolved in an organic solvent (e.g. ethanol or propylene glycol), but if the solvent is water-miscible, when the composition is mixed with gastrointestinal fluid or other aqueous media the cyclosporin will precipitate.
Various methods of overcoming this problem are known in the prior art, but all have certain limitations.
U.S. Pat. No. 4,388,307 discloses compositions comprising cyclosporine in an emulsion preconcentrate that is not water-miscible, but forms an emulsion upon being mixed into gastrointestinal fluids. A commercial product that has been sold under the trademark "Sandimmune" is made according to U.S. Pat. No. 4,388,307, and, more specifically, comprises cyclosporine dissolved in a solvent system comprising ethanol, a vegetable oil and a surfactant. Although this composition was superior to previously known compositions, it still exhibits absorption that is less than the maximum possible and is variable. Also, the use of ethanol has disadvantages, as ethanol is volatile, and the capsules of Sandimmune must be individually packaged in metallic pouches to avoid loss of ethanol by evaporation.
U.S. Pat. No. 5,342,625 discloses compositions that are said to be superior in certain respects to the compositions of U.S. Pat. No. 4,388,307. The compositions of U.S. Pat. No. 5,342,625 comprise, in addition to the cyclosporin, a hydrophilic phase, a lipophilic (i.e. hydrophobic) phase and a surfactant. The hydrophilic phase is either propylene glycol or a pharmaceutically acceptable alkyl or tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkanediol.
The lipophilic phase comprises a solvent which is non-miscible with the hydrophilic phase. and is preferably a fatty acid triglyceride.
It is disclosed that compositions according to U.S. Pat. No. 5,342,625, when added to water, disperse into emuisions with droplet size of less than 2000 .ANG., which is smaller than obtained with prior art compositions, thus leading to improved absorption.
Emulsions with droplet size of less than 2000 .ANG. are defined as "microemulsions". Compositions that, upon addition to water, disperse into microemulsions are called "microemulsion preconcentrates".
A composition made according to the disclosure of U.S. Pat. No. 5,342,625 is now marketed under the trademark "Neoral", in the form of both a soft gelatin capsule which encloses the microemulsion preconcentrate and an oral liquid which is a microemulsion preconcentrate intended to be diluted into an aqueous drink before ingestion.
For both the soft gelatin capsules and the oral liquid, the labelling indicates that the "Neoral" emulsion preconcentrate comprises cyclosporine dissolved in ethanol and propylene glycol as hydrophilic solvents, corn oil as lipophilic (hydrophobic) solvent, and polyoxyl 40 hydrogzenated castor oil as surfactant. It also contains dl-alpha-tocopherol at a level of about one percent by weight as antioxidant, apparently to prevent oxidation of the corn oil.
While "Neoral" does enable improved absorption relative to Sandimmune, it still has certain undesirable properties. Specifically:
1 Ethanol is volatile, so that the soft gelatin capsules have to be packaged individually in metallic pouches to prevent evaporation of the ethanol. PA0 2. The meiting point of the microemulsion preconcentrate is about 20.degree. C. so that it may solidify at room temperature. This means that the oral solution may have to be warmed and melted to be dispensed. Also it cannot be mixed with a cold aqueous drink and is limited to being mixed into warn aqueous drinks. PA0 3. Ethanol contributes to an undesirable taste of the microemulsion preconcentrate, so that, even after dilution into a sweetened drink, there is still a somewhat unpleasant taste. PA0 4. The concentration of cvciosporine is limited to about 100 mg per mL so that a soft gelatin capsules containing 100 mg of cyclosporine is larger than desirable and difficult to swallow. PA0 1. They may be excessively volatile so that a capsule containing the composition must be packed in metallic foil to prevent evaporation. PA0 2. They may exhibit foul taste. PA0 3. They may be excessively hydrophilic so that when the composition is mixed with water they tend to be extracted from the composition causing, some precipitation of the cyclosporin. PA0 4. The melting points of compositions using such solvents may not be low enough to enable the compositions to be dispersed in cold aqueous drinks. PA0 i) Reaction products of natural or hydrogenated vegetable oils and ethylene glycol; i.e., polyoxyethylene glycolated natural or hydrogenated vegetable oils; for example polyoxyethylene glycolated natural or hydrogenated castor oils. Particularly suitable are the products designated in the United States Pharmacopoeia and National Formulary as Polyoxyl 35 Castor Oil and Polyoxyl 40 Hydrogenated Castor Oil, which are available under the trade names Cremophor EL and Cremophor RH40 respectively. Also suitable for use in this category are the various tensides available under the trade names Nikkol, e.g. Nikkol HCO-60. Nikkol HCO-60 is a reaction product of hydrogenated castor oil and ethylene oxide. PA0 ii) Polyoxyethylene-sorbitan-fatty acid esters; e.g. mono- and tri-lauryl, palmityl, stearyl and oleyl esters: e.g. products of the type known as polysorbates and commercially available under the trade name "Tween". PA0 iii) Polyoxyethylene fatty acid esters: for example, polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myrj as well as polyoxyethylene fatty acid esters known and commercially available under the trade name "Cetiol HE". PA0 iv) Polyoxyethylene-polyoxypropylene co-polymers, e.g. of the type known and commercially available under the trade names "Pluronic" and "Emkalyx". PA0 v) Polyoxyethylene-polyoxypropylene block co-polymers, e.g. of the type known and commercially available under the trade name "Poloxamer". PA0 vi) Dioctylsuccinate, dioctylsodiumsulfosuccinate, di-[2-ethylhexyl]-succinate or sodium lauryl sulfate. PA0 vii) Phospholipids, in particular lecithins. PA0 viii) Propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate and so forth. PA0 ix) Bile salts; e.g. alkali metal salts, for example sodium taurocholate. PA0 x) Trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols; e.g. of the type known and commercially available under the trade name Labrafil M1944CS. PA0 xi) Mono-, di- and mono/di-glycerides, especially esterification products of caprylic or capric acid with glycerol. PA0 xii) Sorbitan fatty acid esters; for example, of the type known and commercially available under the trade name Span. PA0 xiii) Pentaerythritol fatty acid esters and polyalkylene glycol ethers; for example pentaerythrite-dioleate, -distearate, -monolaurate, -polyglycol ether and -monostearate as well as pentaerythrite-fatty acid esters. PA0 xiv) Monoglycerides; e.g. glycerol monooleate, glycerol monopalmitate and glycerol monostearate; for example as known and commercially available under the trade names Myvatex, Myvaplex and Myverol, and acetylated, e.g. mono- and di-acetylated mono-glycerides; for example as known and commercially available under the trade name Myvacet. PA0 xv) Glycerol triacetate or 1,2,3)-triacetin; and PA0 xvi) Sterols and derivatives thereof, for example cholesterols and derivatives thereof, in particular phytosterols; e.g. products comprising sitosterol, campesterol or stigmasterol, and ethylene oxide adducts thereof, for examples soya sterols and derivatives thereof, such as known under the trade name Generol.
International Publication Number WO 94/25068 discloses improved compositions in the form of microemulsion preconcentrates in which the principal solvent for the cyclosporin is an alcohol which is selected from alcohols having a boiling point above 100.degree. C. and a solubility in water of under 10 g per 100 g at 20.degree. C. Such alcohols are referred to as a hydrophobic alcohols.
It is disclosed that a hydrophobic alcohol can be used in place of the combination of hydrophilic and hydrophobic solvents.
Preferred hydrophobic alcohols. within the scope of the disclosure of WO 94/25068. are saturated alkyl alcohols having 8 to 14 carbon atoms per molecule, including 1-octyl, 2-octyl, 1-decyl, 1-dodecyl and 1-tetradecyl alcohols.
Compositions according to the disclosure of WO 94/25068 overcome some of the problems of prior art compositions. However, the hydrophobic alcohols have a foul taste so that, even after dilution into a sweetened aqueous drink, there is still an unpleasant taste.
In view of the difficulties with prior art compositions, the object of the invention is to enable microemulsion preconcentrates comprising cyclosporins which use combinations of excidients (i.e. inactive ingredients) not disclosed in the prior art, and therebv overcome some or all of the problems encountered with prior art compositions.